Drugs that inhibit the serotonin transporter, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) and certain members of the Tricyclic Antidepressant (TCA) class of drugs, currently provide efficacy in the treatment of several CNS disorders, including depressive and anxiety disorders. SSRIs and SNRIs are generally perceived by psychiatrists and primary care physicians as effective, well-tolerated and easily administered.
However, with the high incidence of non- and insufficient responders to serotonin enhancing drugs treatment there is impetus for developing adjunct therapies that could enhance the efficacy of these drugs in treatments of CNS disorders, including depressive disorders, bipolar disorders and anxiety disorders.
5-HTP is the immediate precursor of serotonin. 5-HTP as monotherapy is reported to have some clinical efficacy in depression. However, the short half-life of 5-HTP, 4 hours, limits the utility of immediate-release formulations of 5-HTP due to large fluctations in plasma levels, multiple daily doses necessary and/or possibility of nocturnal subtherapuetic plasma levels. 5-HTP treatment in standard, immediate-release formulations has been associated with gastrointestinal adverse events in some patients.
The use of 5-HTP in combination therapy to serotonin transporter inhibitor treatment of depression has been suggested in the prior art (reviewed in Turner E H, Loftis J M and Blackwell A D. “Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan”. Pharmacol Ther. 2006 109(3); 325-38).
However, the relatively short half-life of 5-HTP (about 4 hours) means that dosing needs to be frequent in order maintain a steady plasma level, which inevitably leads to large fluctuations in systemic 5-HTP available for conversion to 5-HT and an inconsistent pharmacodynamic effect. Further, fluctuations in 5-HT levels in patients sustained on SSRIs are associated with mood-fluctuations, Moreover, side effects such as nausea and vomiting associated with 5-HTP treatment are most commonly seen shortly after dosing at a time when systemic 5-HTP levels are peaking, Further, in case of overdosing there is a risk of adverse events—such as serotonin syndrome.
EP 1 627 185 A1 relates to controlled-release formulations containing tryptophan and/or its metabolites.